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Two Beta Blockers Found to Also Protect Heart Tissue

By Duke Medicine News and Communications

A newly discovered chemical pathway that helps protect heart
tissue can be stimulated by two of 20 common beta-blockers,
drugs that are prescribed to millions of patients who have
experienced heart failure.

Researchers from Duke University Medical Center tested 20
beta blockers and found that two of them -- alprenolol and
carvedilol -- could stimulate a pathway recently found to
protect heart tissue.

This finding could guide future drug development and in
particular help heart failure patients, says Howard Rockman,
MD, senior author of the study and chief of the Duke
Cardiology Division.

"To our surprise, we found that these two beta blockers can
actually stimulate the beta receptor to activate a pathway in
the cell that promotes cell survival. We have the first
evidence that these two drugs have greater potential to repair
the heart and to protect it, and possibly even to reverse some
heart damage," Dr. Rockman said.

Until now, scientists believed that all beta-blockers worked
by binding to and blocking the beta-adrenergic receptor, a
molecule on the cell surface that responds to the hormone
adrenalin. Blocking the receptor moderates increases in heart
rate and heart function that could be damaging to patients
whose hearts are already overstressed.

The two beta-blockers identified by the current study also
serve to stimulate a different signaling beta-arrestin pathway.
Beta arrestin is a protein known as an "off-switch" for
beta-adrenergic receptors. These two drugs activated a
beta-arrestin pathway that produces beneficial effects in the
heart tissue.

"These two drugs were found to stimulate the pathway that
produces certain proteins that are protective to the heart,"
Rockman said.

The new study, published online in Proceedings of the
National Academy of Sciences, was funded by that National
Institutes of Health.

"Based on these findings, we hope to design drugs that
strongly bind in this way and activate this pathway," Rockman
said. "We call these drugs biased-ligands or super receptor
blockers, because they are designed to block the harmful
actions of adrenalin at the beta receptor, but at a molecular
level will activate other pathways that protect the cell."
Rockman and colleagues discovered the heart-protection factors
in a study published last year.

He noted that carvedilol (marketed for many years as Coreg
and now as available in generic forms) is known as a very
effective beta blocker, but alprenolol has not been fully
developed as a beta blocker drug for heart failure patients.
Beta blockers now are part of a standard of care for heart
failure patients, who have weakened hearts and cannot tolerate
much adrenalin, which is released all day long in people as
they perform any exertion, even reading an exciting novel.

Every year, 400,000 new cases of heart failure are diagnosed
and the number is growing as the population ages.

"The next step is to test the drugs in animals to learn
which might promote protection and which might cause more
negative effects," Rockman said. "Cell studies can be tricky to
replicate in organisms and we will have to see what happens,
but these cellular results are very exciting and encouraging
and could be a boon to heart failure patients."

Other authors on the study include Il-Man Kim, Douglas
Tilley, Juhsien Chen, Natasha Salazar, Erin Whalen and Jonathan
Violin of the Duke Department of Medicine, in addition to Dr.
Rockman, who is a professor of medicine, cell biology and
molecular genetics at Duke.